Tropomyosin receptor kinase B (TrkB) is activated by the brain-derived neurotrophic factor (BDNF) as its main endogenous ligand, and together they constitute a critical signaling system involved in regulating brain plasticity and restoration. Disruption of this system has been implicated in a number of psychiatric disorders such as depression, anxiety and schizophrenia, and thus TrkB has emerged as an important therapeutic target. However, previous efforts to identify small molecule BDNF mimics and TrkB modulators have not been successful using the established discovery platforms (e.g. high-throughput screening of drug- like compounds and computational design and screening). In this exploratory R21 application, we propose to develop a novel ligand discovery approach, based on the massive combinatorial power of peptide phage display and specific selection conditions, to identify small peptides that modulate the active form of the TrkB receptor. We will develop and validate this new approach, perform phage library screening, identify hit peptide sequences, and conduct preliminary examination of the functional parameters of the top peptides (potency, efficacy, and mode of TrkB modulation in the presence and absence of BDNF). If successful, this project will chart a course for the development of the first robust, small molecule TrkB modulators, and suggest the applicability of this new discovery approach to other challenging molecular targets.